In 1982 physicians first became aware of a new sexually transmitted disease that was associated with an unusual form of cancer (Kaposi""s sarcoma) and a variety of unusual infections. The disease was named acquired immune deficiency syndrome (AIDS), since both these problems reflected a severe deficiency in the helper T cells of the immune system. A retrovirus, called human immunodeficiency virus (HIV), was found to be the causative agent of AIDS. HIV is a member of a family of viruses called lentiviruses that are part of a large group of viruses known as the Retroviridae. Some of the other members of the group are the closely related simian, feline, and bovine immunodeficiency viruses. This group of viruses displays a variety of common features.
The fact that HIV has an extreme tendency to mutate to forms that are resistant to existing antiviral therapies greatly complicates attempts to treat the infection with antiviral drugs. Most of the current research in AIDS is aimed at understanding the life cycle of HIV. AIDS research has been targeted towards inhibition of the virus at different stages of its life cycle.
The molecular target for HIV inhibitors can be broadly classified into the following classes: reverse transcriptase (RT) enzyme, protease enzyme, integrase enzyme, regulatory proteins, and zinc finger domains in the nucleocapsid p7 protein.
The normal flow of genetic information is from DNA to RNA to protein, and hence HIV, which is a retrovirus, must first convert its genomic RNA into a double-stranded DNA in order to start its replication cycle in the host cell. This conversion takes place in the host cell cytoplasm with the help of a viral enzyme called reverse transcriptase (RT) that catalyzes a series of biochemical reactions involved in this process. This makes reverse transcriptase (RT) enzyme an attractive target for HIV inhibitors. HIV RT inhibitors can be broadly classified into nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). The modes of action of these two classes of compounds are different in nature. The nucleoside HIV RT inhibitors are competitive inhibitors that bind to the catalytic site of the enzyme, and their mode of action appears to be through their triphosphates (produced in the cytoplasm of the host cell) that act as RT enzyme inhibitors through incorporation and termination of the growing viral DNA chain. Common nucleoside RT inhibitors are AZT, ddC, ddI, d4T, 3TC, and Abacavir. Non-nucleoside RT inhibitors are non-competitive inhibitors of the RT enzyme; they bind to an allosteric (regulatory) site with a degree of magnitude heretofore not yet observed and influence the RT catalytic site. Hence they are also referred to as second-site inhibitors. In general, at micromolar concentrations NNRTIs inhibit HIV-1 in vitro with minimum or no cytotoxicity but do not inhibit HIV-2 or other retroviruses. NNRTIs include chloro-TIBO, nevirapine, L-697,661, and delavirdine.
1. Field of the Invention
The need and research for active inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is urgent and ongoing. In 1997, U.S. Pat. No. 5,608,085 issued to Baker et al. entitled Synthesis of Optically Active Calanolides A and B and Enantiomers and Related Compounds, which produces anti-HIV-1 or HIV-2 compounds in high yields and in a high degree of purity. Recently, on Dec. 1, 1998, U.S. Pat. No. 5,843,990 issued to Baker et al. entitled Pyran-Chromenone Compounds, Their Synthesis and Anti-HIV Activity, which deals with a class of compounds, particularly optically active compounds of a high degree of purity and free of the corresponding enantiomers, which are highly potent anti-HIV compounds. Application by Deshpande et al. (Ref. 22) also claims this contribution to the scientific community. The effectiveness of these compounds as HIV-1 inhibitors depends on many factors including the degree of affinity these HIV-1 inhibitors have for the enzyme""s allosteric site. In accordance with this invention, novel 2,3-dihydrobenzo[d]isothiazole 1,1-dioxides (sultams) have been discovered that are biologically active, particularly potent HIV-reverse-transcriptase inhibitors. Further, a novel synthesis has been discovered (and a number of variants) by which the sultams are synthesized in an efficient, multi-step process from which the pure enantiomers of the racemates are obtained.
2. Description of Related Art
Publications of interest relating to the subject matter of this invention include:
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All references referred to in this text are incorporated herein by reference in their entirety.
The invention relates to a new class of compounds herein identified generally as xe2x80x9csultamsxe2x80x9d, which may be represented by the following formula V, in FIG. 1, in which numbering of the atoms is started with the sulfur atom of the isothiazole. Two of the rings (rings A and C) are aromatic, and the third is a heterocyclic ring (ring B), a cyclic sulfonamide. Of particular importance are the enantiomerically pure sultams since they are especially potent HIV-1 inhibitors.
Sultams are derivatives of isothiazole 1,1-dioxide (cyclic 5-membered sulfonamides) with an aromatic ring fused at the C-4 and C-5 positions of the isothiazole ring. The investigated sultams have various substituents on the aromatic rings. The nitrogen of the sulfonamide is either tertiary or secondary depending on the nature of the substituents on that atom. On the C-3 position of sultams a variety of aromatic substituents is possible depending on whether aldehydes or ketones are used in the synthesis of the ortho-alkylated sulfonamide IV from FIG. 1. The other substituents on the same carbon can either be hydrogen, when an aldehyde is the reactant, or another substituent defined further below. This quaternary carbon determines the chirality of the resulting sultam. A racemic substance comprised of a pair of enantiomers is generally the product of synthesis and preferably should be separated into the respective enantiomers.
The invention promotes a general method and several synthesis variations more suitable for certain compounds, as described hereinafter. Synthesis variations are taught by the invention that provide a variety of substituents on the rings of the compounds. One such synthesis is better suited for starting compounds with halogen substituents on ring A, which are not compatible with the reaction conditions used in the general method. Another synthesis variation is better suited for compounds which have substituents on ring C which are susceptible to react in subsequent steps of the reaction. These compounds are provided with a protective group for the substituents, which is subsequently removed. Another synthesis variation of the invention yields compounds wherein RQ is CF3. Another synthesis variation of the invention yields compounds in which all the substituent R groups are hydrogens. These syntheses are described in further detail hereinafter. The syntheses of the invention are highly versatile in that the variant best suited for the class of compounds of interest is the synthesis by which one can obtain either a racemic mixture of the pairs of enantiomers or the pure enantiomer, which is the most potent for the control of the target virus.
An objective of the synthesis was to obtain biologically active compounds, especially anti-HIV-1 compounds. The sultam compounds of the invention offer a variety of structural modifications and various possibilities of positioning different substituents in different positions on any one of the rings. It was not known prior to this invention what effect these various substituents and their different positions on the nitrogen, on the stereogenic carbon, and on the ring(s) would have on their biological and, more particularly, their anti-HIV-1 activity.
The invention also provides a new class of such compounds in racemic form which can be resolved into their respective enantiomers. A group of these compounds has an anti-HIV potency heretofore unachieved. In accordance with the invention, an area of the molecule has been identified on which appropriate substituents appear to make a major contribution to a high degree of anti-HIV potency.
The invention also provides a method for treating or preventing viral infections, especially strains of the HIV virus, with the sultams of the invention.
The invention also provides biologically active compositions, which comprise one or more compounds of the invention, in an effective, non-toxic amount in combination with a biologically or pharmaceutically acceptable carrier.
The invention also provides drug combinations of compounds of the invention with HIV protease inhibitors, like ritonavir, saquinavir mesylate, and others.
In still another aspect, the invention provides a method for treating a mammal, particularly a human, infected with a retrovirus, which comprises administering to said mammal an effective nontoxic amount of the composition(s) of the invention.
In summary, the invention contributes to the solution for a serious and urgent world-wide health need which has adverse social and economic consequences.